As one of the most commonly found diseases in male, recently the occurrence of benign prostatic hyperplasia (BPH) is on the sharp rise. Approximately 50% of people in 60s and 90% of people who are older than 85 are known to have BPH and normally they have lower urinary tract symptoms (LUTS) such as nocturia, hesitancy, urinary frequency, and urinary incontinence and surgery is required if urinary tract infection and urinary tract obstruction occur repeatedly (Bertaccini, Vassallo et al. 2001; Wei, Calhoun et al. 2005). As a consequence, even though BPH is not a lethal disorder, it is emerging as an important medical problem of the current aging society as it degrades the quality of life.
Generally, the size of prostate of an adult is around 20 g (±6 g), but, it can grow as large as 40 to 400 g once it becomes abnormal (Foster 2000; Thorpe and Neal 2003). BPH, a histologic disease, in which the prostate is overgrown due to increased number of normal prostatic cells, causes LUTS if an overgrown prostate presses proximal urethra (Jacobsen, Girman et al. 2001; Thorpe and Neal 2003; Liu, Lee et al. 2006). Particularly, BPH induces dramatic changes on stromal cells in the area surrounding the prostatic transition zone and proximal urethra (Foster 2000; Committee 2003), and the ratio of stromal cell to epithelial cell is 2.7:1 in normal condition, whereas it is 4.6:1, once symptom of BPH is present (Foster 2000). The growth of these stromal cells is regulated by adrenergic nerve system and ala subtype receptor is known to be the most predominantly found adrenergic receptor in the prostatic stromal tissue (Foster 2000; Thorpe and Neal 2003).
Meanwhile, although the cause of BPH has never been clearly identified, it is known to be caused by change in male sex hormone due to aging (Isaacs and Coffey 1989). In case of normal prostate, epithelial cell and stromal cell closely interact and thereby the growth and regression of prostate are organically regulated, but in case of BPH, the volume of prostate becomes larger due to rarer apoptosis. Particularly, there are some reports that epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) and transforming growth factor β (TGF-β) are involved. EGF or TGF-β is strong mitosis-stimulating factor and it is believed that EGF mediates the androgen-induced prostatic hyperplasia because a large amount of EGF is included in the prostatic tissues or prostatic secretion (Lee 1996). TGF-β is also increased in the individual having BPH and presumably it is thought to be involved in differentiation of matrix cell into smooth muscle cell (Klinger, Bretland et al. 1999). bFGF is a strong mitosis-stimulating factor that is overexpressed for BPH. bFGF is formed in both of stromal cell and epithelial cell and admittedly, it is reported as the most important factor responsible for the lesion of BPH (Saez, Gonzalez-Baena et al. 1999).
Testosterone and its active form, 5α-dihydroxytestosterone (DHT) also play as an important role for BPH. The DHT, which is formed from testosterone by 5α-reductase type 2, is abundantly found for BPH and it is reported that both testosterone and DHT stimulates the growth of stromal cells in the prostate (Lee, Seong et al. 2001; Thorpe and Neal 2003). Besides, a number of studies are in progress lately in order to confirm the causes of BPH that are associated with dietary intake, exercise, and metabolic diseases (Parsons 2007).
While surgery was conducted as the most commonly practiced method of clinical treatment for BPH in the past, since the late 1980s, clinical treatment has been rapidly diverted to drug administration (Milroy 1990). Nowadays there are α-adrenergic receptor antagonist (α-blockers), 5α-reductase inhibitor, and phytotherapy that are used as remedial drug to treat BPH. In the early stage, monotherapy was conducted, in which drugs are administered to patients and proper drug is chosen and administered to each patient for the purpose of extending the remaining time until surgery by relieving the symptom, but combined treatment was also conducted, in which α-blockers and 5α-reductase inhibitors are co-administered. The drug α-blockers have benefit as they show effects instantly by immediately relieving the symptoms and 5α-reductase inhibitors have benefit as they delay the progression of disease for long, although immediate effects are scarcely shown. As currently used α-blockers, there are alfuzosin, doxazosin, tamsulosin and terzosin. While above four have nearly identical effectiveness, side effects are reported to be different from one another (Committee 2003). α-blockers block the α1-adrenergic receptors that are abundantly expressed in prostate and bladder neck. When α1-adrenergic receptors are blocked, prostatic muscles are relaxed and thereby urination and other symptoms of LUTS are relieved and subsequently the bladder dysfunction caused by BPH can be eliminated (Wykretowicz, Guzik et al 2008). As the most common side effects of this drug, there are dizziness, asthenia, nasal congestion, and orthostatic hypotension (Committee 2003). Dutasteride and finasteride that are used as 5α-reductase inhibitor function in different mechanisms from that of α-blocker. The dutasteride inhibits both 5α-reductase type 1 (mostly expressed in liver and skin) and type 2 (mostly expressed in reproductive organ), whereas the finasteride only inhibits type 2. These mechanisms of action of drugs inhibit the formation of DHT by competing with 5α-reductase. As the abnormal growth of prostate depends on the amount of DHT, the size of prostate is reduced once the amount of DHT is decreased and diseases associated with the BPH can be prevented accordingly (McConnell, Roehrborn et al. 2003). However, it requires 2 month to 1 year of treatment until the accompanied diseases are improved by relying on this drug to reduce the size of prostate (Gormley, Stoner et al. 1992; Kirby, Bryan et al. 1992; Roehrborn, Boyle et al. 2002). Furthermore, erectile dysfunction, hyposexuality, ejaculatory dysfunction and hypertrophy of breast in male may occur as side effects and 3 months after stopping the administration, condition regresses to what it was prior to the treatment. Currently, there are some reports that it is more effective to use the finasteride, a widely administered drug when the size of prostate is larger than 40 g and thus, in case of prescribing this drug, PSA (prostate specific antigen) that is used as the screening factor for prostate cancer is tested beforehand. Also, it is known that combined therapy is more effective if the size of prostate is larger than 40 g and PSA is higher than 4 ng/mL (Committee 2003).
Besides, plant-derived alternative medicines are widely used to treat BPH, and for example, there are saw palmetto, pumpkin seeds, and nettle root.
Although there are a number of therapeutic drugs commensurate with the importance of benign prostatic hyperplasia, due to the limited effectiveness and concerns of side effects such as erectile dysfunction once androgen signaling is inhibited, development of a brand new therapeutic agent that has negligible side effect and confer a fundamental therapeutic effect is urgently required.
One of the prevention and treatment methods of erectile dysfunction is to rely on the blood flow improvement effect of prostaglaind (Wolfson B, Pickett S, Scott N E, DeKernion J B, Rajfer J. 1993 July; 42(1):73-5; Karabulut A, PeL, OzkardeH, AltuU, Erol D. Urol Int 2001; 67(2):160-2). While 15-PGDH is induced by testosterone and DHT in LNCaP cell, an androgen-dependent prostate cancer cell line in a concentration and time dependent fashion, the same result was not observed in PC3 cells, an androgen-independent prostate cancer cell line (Tong M, Tai H H. 2000 Sep. 16; 276(1):77-81). Therefore, if a substance that inhibits androgen signaling can increase the blood flow in the penis by inhibiting the expression or the activity of 15-PGDH and by increasing prostaglandin E2, it is highly possible to reduce the side effect of erectile dysfunction.
Therefore, in the present invention, a Dendropanax morbifera extract was identified to have anti-androgen effect in, an androgen-dependent prostate cancer cell line and based on the idea, in which the side effect of erectile dysfunction can be relieved when the blood flow of the penis is increased by increasing prostaglandin E2 through inhibiting the expression of 15-PGDH, a target gene of androgen receptor, the present invention was finally completed by confirming that the composition including a Dendropanax morbifera hexane extract or a compound derived from the above-described extract is effective for the treatment and prevention of BPH in animal model with BPH induced by testosterone.